Anticholinergic (Antimuscarinic) Medications
Anticholinergic medications relax the bronchial muscles and open up the airways.
Brands and Benefits
Anticholinergics used for COPD include short-acting ipratropium (Atrovent) and long-acting such as tiotropium (Spiriva) or umeclidinium (Incruse) or glycopyrrolate (Lonhala and Seebri) and aclidinium (Tudorza). They are considered standard maintenance medications for COPD.
Long-acting anticholinergic medications are also being given along with inhaled corticosteroids and long-acting beta-agonists. This combination of “triple therapy” reduces the number of exacerbations and improves lung function and quality of life, and it reduces hospitalizations. For people who experience frequent symptoms of COPD, current guidelines support long-acting anticholinergic or beta-agonist inhaler as primary therapy for COPD, supplemented by regular use of inhaled corticosteroids.
Anticholinergic inhalers are also available as a single inhaler or combined with a beta-agonist.
- Combivent contains both ipratropium and the common short acting beta-2-agonist albuterol.
- Anoro Ellipta and Stiolto Respirmat, combined anticholinergic and long-acting beta-2-agonists have been approved for once daily use.
- Recently a once daily combination of inhaled steroid, anticholinergic, and long-acting-beta-2 agonist has been approved (Trelegy Ellipta). Breztri is a similar combination of the three inhaled medications, but is taken twice daily.
Anticholinergics have few severe side effects, and they are less likely to interfere with sleep than the other standard inhaled medications. Side effects include mild cough and dry mouth. Anticholinergics should be used cautiously in people with glaucoma or an enlarged prostate. Some studies have linked the long-acting anticholinergic tiotropium with an increased risk for heart problems, but other studies are reassuring. More research is needed.
When anticholinergics are no longer enough -- and sometimes in place of an anticholinergic medication -- health care providers will prescribe a beta-2-agonist. GOLD guidelines recommend that all patients with persistent symptoms and those with frequent exacerbations take a long-acting beta-2-agonist, usually in addition to a long-acting anticholinergic.
For people whose symptoms come and go, such as with exertion, short-acting bronchodilators are recommended. Albuterol (Proventil, Ventolin, ProAir) is the standard short-acting beta-2-agonist. Others include:
- Levalbuterol hydrochloride (Xopenex)
- Levalbuterol tartrate (Xopenex HFA)
- Pirbuterol (Maxair)
There is no evidence that one beta-2-agonist is better than another. Newer beta-2-agonists, including levalbuterol (Xopenex), have more specific actions than the older medications. Most are inhaled and are effective for 3 to 6 hours.
Long-acting bronchodilators are more effective than short-acting bronchodilators for patients with more significant long-term symptoms. Long-acting beta-2-agonists salmeterol (Serevent) and formoterol (Foradil) are proving to be particularly effective as long-term maintenance therapy for COPD. Newer ones include indacaterol (Arcapta) and olodaterol (Striverdi). They reduce exacerbations by 20% to 25%, they may help prevent bacteria from building up on the airways, and they may offer real improvements in lung function. A nebulized formulation of formoterol is also available for the treatment of COPD.
Some inhalers combine a long-acting beta-2-agonist and a corticosteroid (such as Advair, Seretide, Breo, Dulera and Symbicort). Combining a corticosteroid and long-acting beta-2-agonist reduces exacerbations and improves lung function slightly, but it may increase the risk of pneumonia. Large, long-term studies are needed to assess efficacy and safety over time.
Side effects of both long- and short-acting beta-2-agonists include anxiety, tremor, restlessness, and headaches. People may experience fast and irregular heartbeats. A physician should be notified immediately if such side effects occur, particularly in people with existing heart conditions. Such people face an increased risk of sudden death from heart-related causes. This risk is higher with medications taken by mouth or through nebulizers, but there have also been reports of heart attacks and chest pain (angina) in some people using inhaled beta-2-agonists.
Loss of Effectiveness and Overdose
All long-acting beta-2-agonists come with a boxed warning about an increased risk of asthma-related deaths, but there is no clear evidence that people who have COPD without asthma are at increased risk.
There has been some concern that short-acting beta-2-agonists may become less effective when taken regularly over time. A major concern is that people who perceive beta-2-agonists as being less effective may overuse them. Overdose can be serious and, in rare cases, even life threatening, particularly in people with heart disease or asthma.
Corticosteroids are powerful anti-inflammatory drugs.
Oral corticosteroids are reserved for treating COPD exacerbations, and research finds that they are better than inhaled corticosteroids for this purpose. They speed the time to recovery and reduce the length of the hospital stay, but they do not reduce mortality or affect the long-term progression of the disease. They shouldn't be regularly used for stable disease because of the increased risk of side effects.
Oral corticosteroids are recommended for the initial treatment of people who are hospitalized for COPD exacerbations, yet research finds that most people are given IV steroids instead.
Inhaled corticosteroids (ICS) are the mainstay of asthma therapy. However, their primary use in COPD is combined with other bronchodilators for long-term maintenance. Side effects include oral infections and hoarseness.
A review of evidence has shown that both long-acting beta-agonists (LABA) and inhaled corticosteroids (ICS) yield similar benefits for COPD patients when used as individual therapies. However, long-acting beta-agonists are slightly better at improving lung function, and ICS are slightly more effective at improving quality of life, but increase the risk of pneumonia. Therefore, current guidelines support long-acting beta-agonists as primary therapy, supplemented by regular use of inhaled corticosteroids for people who experience frequent exacerbations.
Theophylline and Other Methylxanthines
Methylxanthines (primarily slow-release theophylline) are also bronchodilators, which relax the airways of the lungs. These drugs are used in people with more severe exacerbations that do not respond completely to corticosteroids, oxygen, or antibiotics.
These drugs do not significantly improve lung function, symptoms, or overall outcomes when used for acute exacerbations. Some experts believe that the modest benefits do not outweigh the risk for toxic side effects from these drugs. Side effects are generally related to the amount of theophylline in the blood. At high doses, side effects can include nausea, anxiety, headaches, insomnia, vomiting, irregular heartbeat, tremors, and seizures.
Administering Inhaled Drugs
Many COPD drugs are inhaled using metered dose inhalers, dry powder inhalers, or nebulizers.
The standard device for delivering COPD medication is the metered-dose inhaler (MDI). This device allows precise doses to be delivered directly to the lungs. A holding chamber, or spacer, improves delivery by giving the patient more time to inhale the medication.
Breath-Activated Dry Powder Inhalers
Dry powder inhalers (DPIs) deliver a powdered form of the drug directly into the lungs. DPIs are as effective as MDIs and are easier to manage, especially for older adults. Humidity or extreme temperatures can affect DPI performance, so these devices should not be stored in humid places (such as bathroom cabinets) or in locations with high temperatures (such as car glove compartments during the summer months).
Other Handheld Inhalers
Respimat delivers a fine-mist spray that is created by forcing the liquid medication through nozzles. It does not use any propellant.
A nebulizer is a device that administers the drug in a fine spray that the patient breathes in. Nebulizers are often used in hospitals or when the patient cannot use an inhaler.
This metered-dose inhaler is a quick way of administering medicine directly into the bronchial passageways to promote clearer breathing.
Medicines That Loosen Lung Secretions
People with persistent coughing and phlegm often use medications that loosen secretions and help move them out of the lungs.
Expectorants, such as guaifenesin (found in common cough remedies), stimulate the flow of fluid in the airways and help move secretions using the motion of cilia (the hair-like structures in the lung) and coughing. Expectorants have not been shown to benefit people with COPD.
Mucolytics contain ingredients that make thick phlegm more watery and easier to cough up. Although mucolytics are not generally recommended for people with COPD, there is some evidence that they may reduce exacerbations by a small amount in some patients with moderate-to-severe COPD who take these medications throughout the winter. The most effective mucolytic is stopping smoking. Anticholinergics appear to decrease the production of mucus. Beta-2-agonists and theophylline improve mucus clearance.
The same drugs used to lower cholesterol may also help protect the lungs of COPD patients, in part due to their anti-inflammatory effects. However, more research is needed to prove these benefits, and to determine the optimal statin dose for COPD patients.
Alpha-1 Antitrypsin Augmentation Therapy
Some people with alpha-1 antitrypsin deficiency are treated with weekly or monthly intravenous infusions of alpha-1 antitrypsin. Research finds that this therapy can't be recommended for COPD patients without alpha-1 antitrypsin deficiency, because the treatment is expensive and there is not enough evidence to show that it reduces exacerbations or improves lung function.
Roflumilast is a medication that can reduce exacerbations in patients with frequent exacerbations. This medication can slightly increase the risk of death in treated patients, so it should be given only to carefully selected patients.
Chronic antibiotics administration to prevent exacerbations is generally not recommended therapy. However, certain types of antibiotics called macrolides may help reduce inflammation. As a result, people who have frequent exacerbations despite maximal treatment may be prescribed azithromycin to be taken daily.
Treating Acute Bronchitis or Pneumonia in COPD Patients
People with COPD are at increased risk for pneumonia, but any lung infection can worsen symptoms and speed deterioration of lung function. People with acute bronchitis or pneumonia who have signs of bacterial infection, such as green or yellow phlegm, usually need antibiotics.
Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the most common causes of pneumonia or exacerbations in people with COPD. The choice of antibiotic depends on the bacteria being treated and bacterial resistance to common antibiotics in the area. Giving preventive antibiotics to people with frequent exacerbations is not recommended because this practice contributes to the development of bacterial resistance.
When it comes to treating acute exacerbations of chronic bronchitis, so-called second-line antibiotics (amoxicillin, clavulanate, macrolides, second- or third-generation cephalosporins, and quinolones) appear to be more effective than, and just as safe, as first-generation antibiotics (ampicillin, doxycycline, and trimethoprim/sulfamethoxazole).
Beta-lactam antibiotics include penicillins, cephalosporins, and some newer medications. They share common chemical features, and all interfere with bacterial cell walls.
Penicillin was the first antibiotic. Many forms of this still-important drug are available today:
- Penicillin derivatives called aminopenicillins, particularly amoxicillin (Amoxil, Polymox, Trimox, Wymox, or any generic formulation), are now the most commonly used penicillins. Amoxicillin is inexpensive, and at one time it was highly effective against S pneumoniae. Unfortunately, bacterial resistance to amoxicillin has increased significantly, both among S pneumoniae and H influenzae. Ampicillin is similar, but it requires more doses and has more severe gastrointestinal side effects than amoxicillin.
- Amoxicillin-clavulanate (Augmentin) is known as augmented penicillin. It works against a wide spectrum of bacteria and is used for more severe exacerbations. An extended-release form is also available.
Many people have a history of allergic reaction to penicillin, but some evidence suggests the allergy may not return in a significant number of adults. Skin tests are available to help determine whether someone with a history of penicillin allergies could tolerate these important antibiotics.
Most of these antibiotics are not very effective against bacteria that have developed resistance to penicillin, and they are only used for more severe exacerbations. They are classified according to their generation:
- Second generation: cefaclor (Ceclor), cefuroxime (Ceftin), cefprozil (Cefzil), and loracarbef (Lorabid).
- Third generation: cefpodoxime (Vantin), cefdinir (Omnicef), cefditoren (Spectracef), cefixime (Suprax), and ceftibuten (Cedax). Ceftriaxone (Rocephin) is an injected cephalosporin. These antibiotics are effective against a wide range of Gram-negative bacteria, and some are also able to treat penicillin-resistant S pneumoniae infections.
Fluoroquinolones (quinolones) interfere with the bacteria's genetic material to prevent them from reproducing. These antibiotics are used for more severe exacerbations.
- "Respiratory quinolones" are currently the most effective drugs available against a wide range of bacteria. These drugs include levofloxacin (Levaquin) and gemifloxacin (Factive). Levofloxacin was the first drug approved specifically for penicillin-resistant S pneumoniae. Some of the newer fluoroquinolones need to be taken only once a day.
- The fourth-generation quinolones moxifloxacin (Avelox) is proving effective against anaerobic bacteria.
S pneumoniae strains that are resistant to the respiratory quinolones are uncommon in the United States, but resistance is increasing.
Many quinolones cause side effects, including sensitivity to light and nervous system (neurologic), psychiatric, and heart problems. Pregnant women should not take this class of drugs. Quinolones also enhance the potency of oral anti-clotting drugs. Quinolones have a "black-box" warning about the risks of tendon inflammation and possible tendon rupture.
Macrolides and Azalides
Macrolides and azalides also affect the genetics of bacteria. These drugs include:
- Azithromycin (Zithromax, Zmax)
- Clarithromycin (Biaxin)
- Roxithromycin (Rulid)
These antibiotics are effective against atypical bacteria such as mycoplasma and chlamydia. All but erythromycin are effective against H influenzae. Macrolides and azalides are also used in some cases for S pneumoniae and M catarrhalis, but there is increasing bacterial resistance to these medicines. Macrolides have been shown to reduce exacerbations with chronic use, irrespective of respiratory cultures.
Tetracyclines inhibit the growth of bacteria. They include doxycycline, tetracycline, and minocycline. They can be effective against S pneumoniae and M catarrhalis, but bacteria that are resistant to penicillin are also often resistant to doxycycline. The side effects of tetracyclines include skin reactions to sunlight, burning in the throat, and tooth discoloration.
Trimethoprim-sulfamethoxazole (Bactrim, Cotrim, and Septra) is less expensive than amoxicillin and is particularly useful for adults with mild bacterial upper respiratory infections who are allergic to penicillin. The drug is no longer effective against certain streptococcal strains. It should not be used in people whose infections occur after dental work, or in people who are allergic to sulfa drugs. Allergic reactions can be very serious.